EP2391624B1 - Azaquinazolinediones inhibiteurs de chymase - Google Patents
Azaquinazolinediones inhibiteurs de chymase Download PDFInfo
- Publication number
- EP2391624B1 EP2391624B1 EP10701310A EP10701310A EP2391624B1 EP 2391624 B1 EP2391624 B1 EP 2391624B1 EP 10701310 A EP10701310 A EP 10701310A EP 10701310 A EP10701310 A EP 10701310A EP 2391624 B1 EP2391624 B1 EP 2391624B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dioxo
- dihydro
- pyrimidin
- ylmethyl
- pyrido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003601 chymase inhibitor Substances 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims description 77
- -1 benzoisothiazolyl Chemical group 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 230000000302 ischemic effect Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 230000009787 cardiac fibrosis Effects 0.000 claims description 3
- 210000004351 coronary vessel Anatomy 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 206010002388 Angina unstable Diseases 0.000 claims description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 208000003037 Diastolic Heart Failure Diseases 0.000 claims description 2
- 206010049694 Left Ventricular Dysfunction Diseases 0.000 claims description 2
- 208000025584 Pericardial disease Diseases 0.000 claims description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 2
- 206010063837 Reperfusion injury Diseases 0.000 claims description 2
- 208000007718 Stable Angina Diseases 0.000 claims description 2
- 206010042957 Systolic hypertension Diseases 0.000 claims description 2
- 208000007814 Unstable Angina Diseases 0.000 claims description 2
- 206010047281 Ventricular arrhythmia Diseases 0.000 claims description 2
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- 208000028208 end stage renal disease Diseases 0.000 claims description 2
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- 208000018578 heart valve disease Diseases 0.000 claims description 2
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 claims description 2
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001424 substituent group Chemical group 0.000 claims description 2
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
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- 102100024539 Chymase Human genes 0.000 description 15
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- 239000012044 organic layer Substances 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
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- 125000004432 carbon atom Chemical group C* 0.000 description 8
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- 235000011152 sodium sulphate Nutrition 0.000 description 8
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Claims (10)
- Composé de la formule (I) :
X1, X2, X3 et X4 sont chacun indépendamment -CHou azote, à condition qu'au moins l'un d'eux soit de l'azote ;E est -COOH ou -COOR, où R est alkyle en C1-C5 ;G est alkyle en C1-C2 ;J est un groupe hétéroaryle éventuellement substitué par 1 à 3 substituants choisis parmi halogène, alkyle en C1-C3 et alcoxy en C1-C3 ;M est un groupe alkyle en C1-C5 éventuellement substitué par 1 à 3 substituants choisis parmi alkyle en C1-C5 et carbocycle en C3-C6 ;ou sel pharmaceutiquement acceptable de celui-ci. - Composé selon la revendication 1, dans lequel :E est -COOH ou -COOR, où R est alkyle en C1-C3 ;G est -CH2- ;J est un groupe hétéroaryle choisi parmi indolyle, benzothiazolyle et benzoisothiazolyle, chacun éventuellement substitué par 1 à 3 groupes alkyle en C1-C3 ;M est alkyle en C1-C3 éventuellement substitué par 1 à 3 substituants choisis parmi alkyle en C1-C5, phényle et cyclopropyle.
- Composé selon la revendication 2, dans lequel .E est -COOH ;J est un groupe hétéroaryle choisi parmi indolyle et benzoisothiazolyle, chacun éventuellement substitué par 1 à 3 groupes méthyle ;M est alkyle en C1-C2 éventuellement substitué par 1 à 3 substituants choisis parmi alkyle en C1-C5, phényle et cyclopropyle.
- Composé selon la revendication 3, dans lequel :
J est un groupe hétéroaryle choisi parmi indolyle ou benzoisothiazolyle, chacun éventuellement substitué par 2 à 3 groupes méthyle ;M est alkyle en C1-C2 éventuellement substitué par 1 substituant choisi parmi alkyle en C1-C5, phényle et cyclopropyle. - Composé selon la revendication 4, dans lequel :
- Composé selon la revendication 5, dans lequel :J =
- Composé selon la revendication 1 choisi parmi
ou sel pharmaceutiquement acceptable de celui-ci.
- Composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un composé selon la revendication 1 et un ou plusieurs supports et/ou adjuvants pharmaceutiquement acceptables.
- Composé selon la revendication 1 destiné à être utilisé dans le traitement d'une maladie ou d'une pathologie choisie parmi une maladie cardiaque chronique (non-ischémique), l'asthme, une maladie respiratoire obstructive chronique, une hypertension pulmonaire, une inflammation pulmonaire, une maladie cardiaque post-infarctus du myocarde (ischémique), un infarctus du myocarde aigu, une lésion consécutive à une perfusion, un dysfonctionnement du ventricule gauche, une fibrose cardiaque, une maladie cardiaque diastolique, une cardiomyopathie hypertrophique, une hypertension systolique, une hypertension résistante, une coronaropathie, une maladie occlusive artérielle périphérique, un anévrisme, une angine stable/instable, une resténose, une néphropathie diabétique, une fibrillation auriculaire/des arythmies ventriculaires, une cardiopathie valvulaire, des maladies péricardiques, une maladie rénale chronique, une insuffisance rénale chronique au stade ultime et un accident vasculaire cérébral, comprenant l'administration d'une quantité thérapeutiquement efficace d'un composé selon la revendication 1.
- Composé selon la revendication 1 destiné à être utilisé dans le traitement d'une maladie ou pathologie nécessitant une procédure médicale choisie parmi un pontage aortocoronarien, une intervention coronarienne percutanée et une implantation d'endoprothèse vasculaire, ledit traitement comprenant en outre l'administration d'une quantité thérapeutiquement efficace d'un composé selon la revendication 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14869309P | 2009-01-30 | 2009-01-30 | |
| PCT/US2010/022052 WO2010088195A1 (fr) | 2009-01-30 | 2010-01-26 | Azaquinazolinediones inhibiteurs de chymase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP2391624A1 EP2391624A1 (fr) | 2011-12-07 |
| EP2391624B1 true EP2391624B1 (fr) | 2013-01-16 |
Family
ID=41818930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP10701310A Active EP2391624B1 (fr) | 2009-01-30 | 2010-01-26 | Azaquinazolinediones inhibiteurs de chymase |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US8501749B2 (fr) |
| EP (1) | EP2391624B1 (fr) |
| JP (1) | JP5587914B2 (fr) |
| WO (1) | WO2010088195A1 (fr) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SA08280783B1 (ar) * | 2007-01-11 | 2011-04-24 | استرازينيكا ايه بي | مشتقات بيريدوبيريميدين كمثبطات pde4 |
| NZ600748A (en) | 2009-12-25 | 2014-06-27 | Daiichi Sankyo Co Ltd | Seven-membered ring compound and pharmaceutical use therefor |
| AR085013A1 (es) | 2011-01-26 | 2013-08-07 | Sanofi Aventis | Derivados de acido 3-heteroaroilamino-propionico sustituidos y su uso como sustancias farmaceuticas |
| CN105899500A (zh) * | 2013-11-08 | 2016-08-24 | 拜耳医药股份有限公司 | 取代的1，2，4-三嗪-3，5-二酮及其作为类糜蛋白酶抑制剂的用途 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4341665A1 (de) * | 1993-12-07 | 1995-06-08 | Basf Ag | Bicyclen-Derivate, ihre Herstellung und Verwendung |
| DE69519921T2 (de) | 1994-07-29 | 2001-06-13 | Suntory Ltd Osaka | Imidazolidin-derivate und ihre verwendung |
| KR100400639B1 (ko) | 1995-04-27 | 2003-12-31 | 미쯔비시 웰 파마 가부시키가이샤 | 복소환식아미드화합물및그의의약용도 |
| US5814631A (en) | 1995-09-28 | 1998-09-29 | Suntory Limited | Quinazoline derivatives and applications thereof |
| WO1998009949A1 (fr) | 1996-09-06 | 1998-03-12 | Nippon Kayaku Kabushiki Kaisha | Nouveaux derives d'acetamide et inhibiteurs de protease |
| CA2321146A1 (fr) | 1998-02-17 | 1999-08-19 | Nippon Kayaku Kabushiki Kaisha | Nouveau derive d'acetamide et son utilisation |
| US6323219B1 (en) | 1998-04-02 | 2001-11-27 | Ortho-Mcneil Pharmaceutical, Inc. | Methods for treating immunomediated inflammatory disorders |
| WO2000005204A1 (fr) | 1998-07-23 | 2000-02-03 | Shionogi & Co., Ltd. | COMPOSES DE β-LACTAME MONOCYCLIQUES ET INHIBITEURS DE LA CHYMASE LES RENFERMANT |
| US20040122042A1 (en) | 2001-08-24 | 2004-06-24 | Hidenori Urata | Drugs containing chymase inhibitor and ace inhibitors as the active ingredients |
| WO2005030217A1 (fr) * | 2003-09-23 | 2005-04-07 | Merck & Co., Inc. | Inhibiteurs du canal potassique a base de quinazoline |
| ATE493421T1 (de) | 2004-01-23 | 2011-01-15 | Janssen Pharmaceutica Nv | Neue inhibitoren von chymase |
| JP4865702B2 (ja) | 2004-05-03 | 2012-02-01 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | サイトカイン阻害剤 |
| WO2008147697A1 (fr) * | 2007-05-22 | 2008-12-04 | Boehringer Ingelheim International Gmbh | Inhibiteurs de benzimidazolone chymase |
| US8377949B2 (en) | 2007-08-16 | 2013-02-19 | Boehringer Ingelheim International Gmbh | Quinazolinedione chymase inhibitors |
-
2010
- 2010-01-26 JP JP2011548206A patent/JP5587914B2/ja active Active
- 2010-01-26 US US13/146,765 patent/US8501749B2/en active Active
- 2010-01-26 EP EP10701310A patent/EP2391624B1/fr active Active
- 2010-01-26 WO PCT/US2010/022052 patent/WO2010088195A1/fr active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010088195A1 (fr) | 2010-08-05 |
| EP2391624A1 (fr) | 2011-12-07 |
| JP2012516335A (ja) | 2012-07-19 |
| US8501749B2 (en) | 2013-08-06 |
| JP5587914B2 (ja) | 2014-09-10 |
| US20120108597A1 (en) | 2012-05-03 |
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